An MRI (magnetic resonance imaging) apparatus is an apparatus which can obtain a nuclear magnetic resonance signal and a positional information from an hydrogen atom contained in water or the like in a measurement sample, by arranging the measurement sample in a static magnetic field having high strength (several hundreds millitesla to several tesla), and applying electromagnetic wave pulses of several dozen to several hundreds megahertz to the measurement sample with gradient magnetic field pulses. When a living body is selected as a measurement sample, the MRI apparatus can noninvasively provide a morphological image in the inner part of the living body. The MRI diagnosis apparatus which is used for a human body of the measurement sample has been widely utilized in the clinical field, and the morphological image obtained thereby exerts its strength for a diagnosis.
A hydrogen atom contained in a metabolic substance in the living body has different nuclear magnetic resonance frequencies according to their chemical environments (chemical bond states) respectively, and the difference is observed as a deviation among the resonance frequencies of the nuclear magnetic resonance signals. The deviation is generally referred to as a chemical shift. MRS (Magnetic Resonance Spectroscopy) is a method for directly detecting the metabolic substance in the living body as a nuclear magnetic resonance spectrum generally by using the deviation of the chemical shift, and 1H MRS (1H Magnetic Resonance Spectroscopy) is the MRS which uses a hydrogen-1 as a target. Unlike the morphological image obtained through a typical MRI, 1H MRS can noninvasively detect an endogenous metabolic substance and the positional information as well, if necessary, and accordingly is expected to be also applied to various diagnoses. A study is continued which is directed at evaluating, for instance, a prostatic cancer by measuring a ratio of choline, creatine and citric acid at sites of an object for an examinee through 1HMRS (for instance, see Journal of Experimental & Clinical Cancer Research), 24 (4), 523 (2005)). In addition to the above study, such studies on 1HMRS are performed as to relate to brain tumor, brain infarction, and brain metabolism. Furthermore, 1H MRSI (1H Magnetic Resonance Spectroscopy Imaging) is also known which observes 1H MRS as an imaged figure.
The 1HMRS has the highest sensibility, because the hydrogen-1 having a nuclear spin has a natural isotope abundance ratio of approximately 100% and has a large nuclear gyromagnetic ratio. However, there are many substances containing a hydrogen atom including water in the living body, so that when a specific substance of interest is tried to be observed, a contamination signal from surrounding tissues becomes a problem. The 1HMRS has a narrow band of observed frequency, and often has a peak in which a plurality of peaks is overlapped.
On the other hand, 13CMRS (13C Magnetic Resonance Spectroscopy) is also known which uses a nuclear magnetic resonance signal of a carbon-13 that is an isotope of carbon. The 13CMRS has a wider band of observed chemical shift range than that of 1HMRS, has excellently separated peaks, and can analyze a metabolic substance or the like more in detail. However, the carbon-13 having the nuclear spin has a natural isotope abundance ratio of only about 1.1% in contrast to that of the hydrogen-1, and so that the 13CMRS shows extremely lower signal-to-noise ratio than 1HMRS.
Then, it is effective to observe 13CMRS by combining an isotope-labeled compound of a carbon-13 with a probe agent. A usable probe agent includes, for instance, a glucose which originally exists in the living body and makes its carbon atom isotope-labeled with the carbon-13.
In an MRI imaging operation, an MRI contrast agent or the probe agent is occasionally used. The MRI contrast agent can increase an amount of information for diagnosis by emphasizing a state of blood vessel, a state of vascular flow in an organ, or a state of vascular flow or features of a diseased site on the MRI image. In addition, there is a case in which a disease cannot be found without using the contrast agent. An MRI contrast agent or a probe agent to be mainly employed includes a gadolinium formulation which is prepared by making a gadolinium ion and an organic compound form a complex and stabilizing the complex, or an iron formulation such as an iron oxide fine particle. Because these formulations are paramagnetic, the formulations give an influence on a relaxation time and a chemical shift of the nuclear magnetic resonance signal emitted from a region in which the formulation exists, and give a contrast to the MRI image. However, these formulations do not originally exist in the living body, and need to be largely administered so as to present the contrast. Accordingly, there is a problem that an influence to the living body is feared. In contrast to this, the method of employing a compound which originally exists in the living body and is isotope-labeled with the carbon-13 as the probe agent has an advantage of giving little influence to the living body even when the compound is administered in large quantities to some extent. Furthermore, the method is an effective means for obtaining useful information on a distribution and concentration of the above described probe agent in the living body due to metabolism or the like. The method also can compensate a low degree of sensitivity due to a low natural isotope abundance ratio of the carbon-13.
On the other hand, because a carbon-13 has a nuclear gyromagnetic ratio of only ¼ of the nuclear gyromagnetic ratio of a hydrogen-1, the compound isotope-labeled (label) with the carbon-13 has a problem of showing lower signal-to-noise ratio than 1HMRS even when the compound is used as the probe agent. In order to solve the problem, a method is proposed which improves signal-to-noise ratio by utilizing a magnetization transfer occurring between a hydrogen-1 and a carbon-13. This is a method of irradiating the hydrogen-1 with a radio wave having a frequency resonant with the hydrogen-1 to create high polarization state of the hydrogen-1, then irradiating the carbon-13 with a radio wave having a frequency resonant with the carbon-13 to transfer the high polarization state of the hydrogen-1 to the carbon-13, and observing the nuclear magnetic resonance signal of the carbon-13. This is one of techniques referred to as a double resonance method. Known representative techniques among such methods are INEPT (Insensitive Nuclei Enhanced by Polarization Transfer) and DEPT (Distortionless Enhancement by Polarization Transfer). When (T) is defined as a repetition time of measurement, γ1H and T1H are defined as a gyromagnetic ratio of the hydrogen-1 and a longitudinal relaxation time of the hydrogen-1 respectively, and γ13C and T13C are defined as a gyromagnetic ratio of the carbon-13 and a longitudinal relaxation time of the carbon-13 respectively, sensitivities of the nuclear magnetic resonance signal of the carbon-13 are different according to an observation method, as follows. Specifically, sensitivity in a case where the carbon-13 is directly observed is γ13C5/2 (1−e−T/T13C). On the other hand, sensitivity in a case where the carbon-13 is observed with the use of the magnetization transfer is (γ1H/γ13C)3/2 (1−e−T/T1H). Accordingly, the method of using the above described magnetization transfer can show approximately 4 times higher sensitivity in principle.
A method is also known which transfers the high polarization state of a hydrogen-1 to a carbon-13, further transfers the polarization back to the hydrogen-1 and observes the nuclear magnetic resonance signal of the hydrogen-1. Known representative methods of using the magnetization transfers twice as describe above include HSQC (Heteronuclear Single Quantum Coherence) and HMQC (Heteronuclear Multi Quantum Coherence). In a case where the method is employed, the sensitivity becomes γ1H5/2 (1−e−T/T1H). The obtained sensitivity is further higher than the sensitivity in a case where the carbon-13 is observed with the use of the magnetization transfer. Measurement examples of 1H MRS using HSQC and HMQC are reported, which use the magnetization transfers between the hydrogen-1 and the carbon-13 twice (see Magnetic resonance in medicine, 43, 525 (2000), Japanese Patent Application Laid-Open No. H10-137214, Japanese Patent Application Laid-Open No. H09-262221 and Japanese Patent Application Laid-Open No. H11-089814).
The magnetization transfer between nuclei does not occur unless each nucleus to be mutually magnetization-transferred has a nuclear spin. Therefore, when considering the magnetization transfer between a hydrogen atom and a carbon atom, only signal of the hydrogen atom bonded to the carbon-13 is observed, and the nuclear magnetic resonance signal of the hydrogen atom bonded to the carbon-12 is not detected. Accordingly, when the 1H MRS is measured by using the above described HSQC or HMQC technique after having made a living body take a probe agent isotope-labeled with a carbon-13, the nuclear magnetic resonance signal of the hydrogen atom mainly coming from the compound isotope-labeled with the carbon-13 is detected. However, because a carbon-13 exists in nature at a ratio of 1.1%, a substance having a hydrogen atom bonded to a carbon-13 exists in some rate in sites to be observed, other than the probe agent. Accordingly, the nuclear magnetic resonance signal of the hydrogen atom observed from these substances becomes a contamination signal, which becomes a factor of decreasing signal-to-noise ratio.
Furthermore, when a distribution and a concentration of the probe agent isotope-labeled with the carbon-13 in the living body is observed with the above described 1H MRS, the 1H MRS causes a problem of needing to separate a nuclear magnetic resonance signal of a compound in the probe agent from a nuclear magnetic resonance signal of a compound which has the same chemical structure as the compound in the above described probe agent and originally exists in a living body (compound which originally has the carbon-13 at the same position as that of the carbon-13 in the probe agent). In other words, when glucose isotope-labeled with the carbon-13 is used for the probe agent, 1.1% of glucose which originally exists in the living body is observed with the above described 1HMRS, because the glucose contains the carbon-13 at the same position as that of the carbon-13 in the probe agent. Suppose that when the isotope-labeled probe agent has been taken in the living body, the concentration is considerably diluted. Then, the signal coming from 1.1% of the glucose, which originally exists in the living body, is an obstacle in a process of evaluating the distribution and the concentration of the glucose isotope-labeled with the carbon-13.
By the way, a technique with the use of the magnetization transfer occurring between three nuclear spins each having different resonance frequencies is a triple resonance method. The triple resonance method is used mainly for a molecular structure analysis such as protein or peptide, and a HNCA technique, a HN(CO)CA technique and a HNCO technique are known as representative examples. For instance, the HNCA technique (see Journal of Magnetic Resonance, 89,4965 (1990), for instance) transfers magnetization from the hydrogen-1 in an amide bond to a nitrogen-15 bonded thereto, further to a carbon-13 in an alpha position bonded thereto, and further transfers the magnetization back to the hydrogen-1 through the reverse path. By transferring the magnetization in the above described way, the nuclear magnetic resonance signal of the hydrogen-1 which has passed the above described magnetization transfer path is observed in a form of a two-dimensional or a three-dimensional spectrum, and information on a main chain sequence of protein, peptide or the like can be obtained therefrom. In addition, Magnetic. Resonance in. Chemistry, 31, 1,021 (1993) also reports a triple resonance method among a hydrogen-1, a carbon-13 and a phosphorus-31.
A generally known triple resonance method is directed at analyzing information on a molecular structure such as a main chain sequence of protein, peptide or the like. Accordingly, the triple resonance method includes measuring protein, peptide or the like in a form of a solution, thereby observing the information in a form of a two-dimensional or three-dimensional spectrum, and accordingly performing a plurality of chemical shift evolutions across axes of resonance frequencies for three nuclides. Therefore, it is difficult to obtain spatial positional information such as an image of a substance with the generally known triple resonance method. The triple resonance method needs a plurality of chemical shift evolutions across axes of resonance frequencies for three nuclides in order to obtain an image of a substance, and accordingly needs an extremely long period of measurement time when trying to obtain the further spatial image in three axial directions. For the above described reason, the generally known triple resonance method is not suitable for a method of directly measuring the living body itself, and detecting and imaging a metabolic substance or the like.
On the other hand, the triple resonance method used in the present invention is used for selectively detecting the isotope-labeled probe agent, and does not need to perform a plurality of chemical shift evolutions across axes of resonance frequencies for three nuclides. Incidentally, WO 98/57578 discloses a concept on MRI with the use of the triple resonance method, but does not disclose its specific technology.